Alzheimer disease. (AD) is a disorder of the later decades of life characterized by dementia. In clinical terms, it consists of a diffuse deterioration of mental function, primarily in thought and memory and secondarily in feeling and conduct. AD has also been used to designate dementia appearing before the age of 65 years.
The true incidence of the disorder is unknown, although recent data suggest that the incidence of all dementia in the U.S. population may be over 100 cases per 100,000, with its prevalence being over 550 per 100,000. AD probably affects at least 30 to 50% of patients with dementia, and in the United States there may be over one million individuals with severe dementia and several million more with mild to moderate dementia. It has been estimate that 1 out of every 6 persons over the age of 65 in the United States suffers from moderate dementia, and a majority of patients in nursing home populations are affected with the disorder. The average age of onset is between 70 and 79 years, but without better information on the population at risk, a more accurate statement is not presently possible. The incidence of the syndrome clearly increases with advancing age. A family history of AD is present in 5 to 10% of the patients.
The major abnormalities observed in individuals suffering from AD include the deposition of .beta.-amyloid peptides (A.beta.) in the extra-cellular space, the massive loss of cortical neurons and the accumulation of paired helical filaments (PHFs) in the neurofibrillary tangles (NFTs), dystrophic neurites and neuropil threads (NTs). The subunit proteins of PHFs are derivatized forms of CNS .tau. proteins known as, interchangeably, A68 or PHF .tau.. Relative to adult CNS .tau. proteins, PHS .tau. is excessively phosphorylated and far more resistant to proteolysis than its normal counterpart, but fetal CNS .tau. is phosphorylated at similar sites.
Despite intense research into the pathological significance of A.beta. deposits for over a decade, the role of A.beta. in the pathogenesis of AD remains enigmatic. Indeed, abundant deposits of A.beta. occur in the brains of elderly individuals who show no antemortem evidence of dementia. On the other hand, the presence of mutations in the APPs within or flanking the A.beta. domain in a subset of familial AD kindred provide circumstantial evidence for the involvement of A.beta. and APPs in the etiology of some forms of AD.
In contrast, considerable information is available on the basic biology, pathology and normal functions of adult and fetal CNS .tau. proteins. CNS .tau. proteins are a group of developmentally regulated low molecular weight microtubule-associated proteins that bind to MTs. They function to stabilize MTs in the polymerized state and facilitate the polymerization of tubulin into MTs. Normal adult human brain .tau. consists of six alternatively spliced proteins encoded by the same gene, and each .tau. isoform contains either 3 or 4 consecutive MT binding motifs. Further, human .tau. isoforms differ with respect to the presence or absence of inserted sequences in the amino-terminal third of .tau. that are 29 or 58 amino acids in length. So-called "fetal" .tau. is the shortest .tau. isoform, and it is expressed early in the developing human nervous system, while all 6 alternatively spliced .tau. isoforms (including "fetal" CNS .tau.) are expressed in the adult human brain.
There is a need for a method of stabilizing microtubules in the presence of A68 protein which are undergoing microtubule destabilization due to a deficiency in normal CNS tau protein that stabilizes microtubule polymerization. There is a need for a method of stabilizing microtubules in the presence of A68 protein in cells undergoing microtubule destabilization due to a deficiency in normal CNS tau protein that stabilizes microtubule polymerization.